title: Design, synthesis, and biological evaluation of indole-2-carboxamides: a promising class of antituberculosis agents.
abstract: Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One of the hits, indole-2-carboxamide analog (1), had low micromolar potency against Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and low aqueous solubility. Structure-activity relationship studies revealed that attaching alkyl groups to the cyclohexyl ring significantly improved Mtb activity but reduced solubility. Furthermore, chloro, fluoro, or cyano substitutions on the 4- and 6-positions of the indole ring as well as methyl substitution on the cyclohexyl ring significantly improved metabolic stability. 39 and 41, the lead candidates, displayed improved in vitro activity compared to most of the current standard TB drugs. The low aqueous solubility could not be mitigated because of the positive correlation of lipophilicity with Mtb potency. However, both compounds displayed favorable oral pharmacokinetic properties in rodents and demonstrated in vivo efficacy. Thus, indole-2-carboxamides represent a promising new class of antituberculosis agents.
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670.
authors.forename: Ravinder Reddy
authors.initials: RR
authors.lastname: Kondreddi
authors.forename: Jan
authors.initials: J
authors.lastname: Jiricek
authors.forename: Srinivasa P S
authors.initials: SP
authors.lastname: Rao
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Luis R
authors.initials: LR
authors.lastname: Camacho
authors.forename: Ranga
authors.initials: R
authors.lastname: Rao
authors.forename: Maxime
authors.initials: M
authors.lastname: Herve
authors.forename: Pablo
authors.initials: P
authors.lastname: Bifani
authors.forename: Ngai Ling
authors.initials: NL
authors.lastname: Ma
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.forename: Thomas
authors.initials: T
authors.lastname: Dick
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: C587008:4,6-dichloro-N-(4,4-dimethylcyclohexyl)-1H-indole-2-carboxamide; D000995:Antitubercular Agents; D007211:Indoles